Antimicrobial polmerizable composition, the polymer and article obtained from the same

ABSTRACT

An antimicrobial polymerizable composition comprising an ethylenically unsaturated monomer, a specific monomer having antimicrobial activity and a polymerization initiator. The composition gives, upon polymerization, a polymer having permanent antimicrobial property, which is very useful for medical articles, in particular dental materials.

This application is a continuation of application Ser. No. 07/962,736,filed Oct. 19, 1992 now U.S. Pat. No. 5,408,022.

BACKGROUND OF THE INVENTION

1. Field of the invention

The present invention relates to a polymerizable composition that canyield an unreleasable antimicrobial polymer and, more specifically, to apolymerizable composition capable of yielding an unreleasableantimicrobial polymer from which the antimicrobial component is notreleased, and the polymer and medical articles obtained from thecomposition.

The medical articles produced according to the present inventionincludes artificial blood vessel, artificial skin, wound-coveringmaterials, Catheter, suture, dental materials (adhesives, coatingagents, composite resins and the like), contact lens, bone cement andthe like.

2. Description of the Prior Art

Polymers having antimicrobial property are known. For example, polymerscontaining a releasable antimicrobial component have this property. Ithas been considered necessary for development of antimicrobial propertythat the antimicrobial component used be entrapped by bacteria orenclose them to kill or inactivate them. For this purpose, it has beenconsidered necessary that the antimicrobial component elute, i.e. bereleased, to contact with bacteria unrestrictedly. For example,"Synthesis and Antibacterial Activities of Copolymers Having aQuaternary Salt Group", that is on pages 934-939 of METAL, INORGANIC ANDPOLYMER MATERIALS, the 9th series, literature of research anddevelopment issued from Agency of Industrial Science and Technology,reports that an acrylonitrile copolymer containing ammonium chloridegroups is released to develop an antimicrobial property against Bacillussubtilis or Staphylococcus aureus. Japanese Patent Application Laid-openNo. 201806/1987 discloses an antimicrobial dental composition containingcetylpyridinium chloride that is a known cationic surfactant.

With releasing of anitimicrobial component, however, the antimicrobialactivity decreases with elapse of time and is lost when the component isout. Antimicrobial components often give hazardous action to normaltissue and they, having been released, migrate also to normal tissue,whereby it is impossible to prevent the hazardous action completely.Incorporation of antimicrobial agents often causes the matrix todecrease its mechanical properties.

The antimicrobial activity in the field of dental materials is brieflydescribed below. Caries, which is a representative dental disease,develops by dissolution of enamel with acids produced by bacteria in theoral cavity. Streptococcus mutans is mentioned as an important bacteriumcausing caries. Periodontitis, which is a disease of periodontal tissue,develops also by bacteria present in the oral cavity. It is importantfor preventing either of these diseases to prevent the bacteria fromforming plaque on the surface of dentin or to remove the plaque onceformed, quickly. Regular toothbrushing is recommended to these ends.

Where a dental prosthesis has been conducted to fill or restore a carieswith a dental material such as resin or composite resin, it is alsoimportant, for the purpose of preventing development of secondary cariesor periodontitis, to remove plaque that readily forms on the surface ofthe material caused by adhesion of bacteria.

To prevent caries, known practice is topical application of fluoride,i.e. application to dentin of an acid phosphoric fluoride (APF) solutionor a diamine silver fluoride solution, which improves the acidresistance of enamel. Several attempts have also been made, while payingattention to the dental material used, to prevent plaque from depositingon, in particular, the very material. Thus, incorporation ofantimicrobial agents in dental materials has been attempted, and therehave been reported, for example, a composite resin incorporatingchlorohexidine (K. Takemura et al, The Japanese Journal of ConservativeDentistry, Vol. 26, (2), 540-547, 1983), calcium phosphate-based cementincorporating metronidazole (M. Iwaku et al, The Japanese Journal ofConservative Dentistry, Vol. 30, (5), 1444-1448, 1987).

Such simple incorporation of an antimicrobial agent in dental material,however, cannot assure satisfactorily durable antimicrobial activity,since the agent is released out in a short period of time. Theincorporation further has the problem of decreasing the mechanicalproperties of the matrix material.

Furthermore, releasing of an antimicrobial agent contained in a dentalcomposition may, while influencing the surface of the composition, badlyinfluence bacterial flora surrounding the composition in the oralcavity.

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide anantimicrobial dental composition that does not allow its antimicrobialcomponent to be released out.

Thus, the present invention provides a polymerizable compositioncomprising an ethylenically unsaturated monomer, at least one mono-, di-or trifunctional monomer selected from the group represented by thefollowing general formulas I through III and having antimicrobialactivities and a polymerization initiator ##STR1## wherein R, representsa hydrogen atom or a methyl group, R₂ represents an alkylene grouphaving 2 to 18 carbon atoms, X represents an oxygen atom, a sulfur atomor an imide group and Y, Y' and Y" represent any one selected from thefollowing respective formulas: ##STR2## wherein R₃ represents a hydrogenatom or an alkyl group having 1 to 18 carbon atoms, R₄ represents amethyl group, a ethyl group or a hydroxyethyl group and Z represents achlorine atom or bromine atom.

The present invention further provides an antimicrobial linear copolymerobtained by polymerizing a monofunctional ethylenically unsaturatedmonomer and a monofunctional antimicrobial monomer represented by theabove general formula I, in the presence of a polymerization initiator.The present invention also provides an antimicrobial crosslinkedcopolymer obtained by polymerizing a mono- or multifunctionalethylenically unsaturated monomer and an antimicrobial monomerrepresented by the above formula I, II or III, in the presence of apolymerization initiator.

The present invention still further provides an unreleasableantimicrobial medical article obtained by shaping the above linearpolymer and, also, an unreleasable antimicrobial medical articleobtained by shaping the above crosslinked polymer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The polymer obtained from the composition of the present invention hasantimicrobially active regions, which do not dissociate or are releasedout from the polymer. The antimicrobial activities developed by thestructure of the polymer of the present invention cannot be explainedfrom conventional concept. It is, however, considered to be due to someaction exerted by the antimicrobial regions against bacteria that havecome into contact with the polymer and killing or inactivating them.

Concrete examples of the antimicrobial compound used in the inventionare as follows. ##STR3## wherein R₁, X and Z are as defined above.##STR4## wherein R₁ and Z are as defined above. ##STR5## wherein R₁ andZ are as defined above.

It is desirable that the above antimicrobial compounds be contained inthe composition in an amount of 0.01 to 50% by-weight based on theweight of the composition. If the content exceeds 50% by weight, theresulting polymer will have low physical properties.

The composition of the present invention is to produce the intendedpolymer, and can be supplied as it is to customers who then polymerizeit upon use. Or, for those uses that require polymers, the compositioncan also be supplied in the form of polymers.

Linear polymers, obtained by polymerizing monofunctional monomers, arebest fit for uses requiring good thermoplasticity or ready moldability.For uses requiring high hardness, thermal resistance and strength,suitable are crosslinked polymers obtained by polymerizing a monomermixture comprising at least one multifunctional monomer. The type andamount of the multifunctional monomer may be properly selected dependingon the intended use of the resulting polymer.

The polymers obtained according to the present invention haveantimicrobial properties and hence they are suitably used for medicalitems. They are also, naturally, usable for goods for daily use andindustrial purposes requiring antimicrobial properties.

Shaped articles obtained according to the present invention includemembranes, films and other shapes obtained by coating or injecting in amold the composition and then polymerizing it. They further includefilms, coating, fibers, hollow fibers, hollow bodies and like shapesobtained by forming the linear polymer or partially crosslinked polymersby known forming processes.

More concrete uses intended by the present invention are now described.Dental applications include composite resins, adhesives, pit and fissuresealants, prosthetics, denture bases, coating materials, resins fortemporary restoration, resin-based cements and artificial tooth roots.Since the surface of dental materials is always exposed in the dentalcavity, bacteria grow thereon to a large extent. The effect of thepresent invention is therefore most suitably produced in the field ofdental applications. Applications in orthopedics are bone cement,artificial bone, artificial joint and the like. With respect toartificial bones, the composition of the present invention is moresuitably used as a coating material for them. For surgery, suture,artificial vessel, wound-covering material, artificial skin and the likemay be mentioned. For opthalmology, there may be suitably used softcontact lenses and hard contact lenses comprising the polymer of thepresent invention. In particular, the polymer is better used for softcontact lenses having high water content, which often suffer from growthof bacteria. Besides the above, the polymer of the present invention isused for disposable tubes for medical purposes, catheters and the like.

The above items may comprise, in addition to the components describedabove, other additives such as organic polymers, fillers, stabilizersand stains (pigments) according to the intended uses.

Important ones among these components in the present invention are nextexplained.

Examples of the ethylenically unsaturated monomer used in the inventionare esters of an acid such as α-cyanoacrylic acid, (meth)acrylic acid,urethane(meth)acrylic acid, crotonic acid, cinnamic acid, sorbic acid,maleic acid or itaconic acid, with a mono- or dihydric alcohol;(meth)acrylamides such as N-isobutylacrylamide; vinyl esters ofcarboxylic acids, such as vinyl acetate; vinyl ethers such as butylvinyl ether; mono-N-vinyl compounds such as N-vinylpyrrolidone andstyrene derivatives. Particularly suitable for the purpose of thepresent invention are the following: mono- ormultifunctional(meth)acrylates and urethane(meth)acrylates. The terms(meth)acrylic acid and (meth)acrylate herein mean acrylic acid and/ormethacrylic acid, and acrylate and/or methacrylate, respectively.

i) Monofunctional monomers

Methyl (meth)acrylate, n- or i-propyl (meth)acrylate, n- i- or t-butyl(meth)acrylate, 2-hydroxyethyl (meth)acrylate, siloxanyl methacrylateand the like.

ii) Difunctional monomers

Compounds represented by the general formula ##STR6## wherein nrepresents an integer of 3 to 20 and R represents a hydrogen atom or amethyl group.

Examples: Di(meth)acrylates of propanediol, butanediol, hexanediol,octanediol, nonanediol, decanediol, eicosanediol and the like.

Compounds represented by the general formula ##STR7## wherein nrepresents an integer of 1 to 14 and R represents a hydrogen atom or amethyl group.

Examples: Di(meth)acrylates of ethylene glycol, diethylene glycol,triethylene glycol, tetraethylene glycol, dodecaethylene glycol,tetradecaethylene glycol, propylene glycol, dipropylene glycol,tetradecapropylene glycol and the like; glycerine di(meth)acrylate;2,2-bis [4- (3-methacryloyloxy-2-hydroxypropoxy)phenyl]propane("Bis-GMA"); bisphenol-A di(meth)acrylate, neopentyl glycoldi(meth)acrylate; 2,2-di(4-methacryloyloxypolyethoxyphenyl)propane(having 2 to 10 ethoxy groups in a molecule), 1,2-bis(3-methacryloyloxy-2-hydroxypropoxy)butane and the like.

iii) Tri- or more functional monomers

Trimethylolpropane tri(meth)acrylate, pentaerythritoltetra(meth)acrylate and the like.

iv) Urethane (meth)acrylate

Examples are reactions products of 2 moles of a (meth)acrylate having ahydroxyl group and 1 mole of a diisocyanate and those of an urethaneprepolymer having an NCO group at each of its molecular ends and a(meth)acrylate having a hydroxyl group. The products of these reactionshave the following structure. ##STR8## wherein R¹ represents a hydrogenatom or a methyl group, R² represents an alkylene group and R³represents an organic residue.

Polymerizable monomers having an acid group such as phosphoric acidgroup or carboxylic acid group are also usable for the purpose of theinvention, and their examples are as follows.

i) Those containing phosphoric acid group ##STR9## wherein R¹ and R²each represents a hydrogen atom or a methyl group and R³ and R⁴ eachrepresents an organic residue. ##STR10## wherein R¹ represents ahydrogen atom or a methyl group, R² represents a hydrogen atom or aphenyl group and n represents an integer of 2 to 14.

ii) Reaction products of a (meth)acrylate having a hydroxyl group as abranch and phosphoryl chloride and their example are as follows.##STR11## iii) Monomers having carboxyl group ##STR12## and theiranhydrides ##STR13## wherein R¹ represents a hydrogen atom or a methylgroup and R² represents an organic residue. A concrete example is4-methacyloyloxyethyl trimellitate anhydride.

Other examples are represented by the following formula ##STR14##wherein R¹ represents a hydrogen atom or a methyl group and R²represents an organic residue. An example is ##STR15##

Examples of the filler which may, as required, be added to thecomposition of the present invention are quartz powder, alumina powder,hydroxyapatite, calcium carbonate, fluoroaluminosilicate glass, bariumsulfate, titanium oxide, zirconia powder, glass powder, microfine silicaand organic composite fillers containing organic components andinorganic components. Powder of polymers such as polymethylmethacrylate, polystyrene and polyvinyl chloride may also be, ifnecessary, added. Examples of the glass are silica glass, soda silicateglass, boro-silicated glass, barium boroalumino-silicated glass,aluminosilicate glass, strontium boroalumino-silicated glass, syntheticsilica and titanium silicate glass.

It is desirable that the inorganic filler used in the present inventionbe surface-treated before use. Examples of surface-treating agentsusable for this purpose are organosilicon compounds such asγ-methacryloxypropyltrimethoxysilane, vinyltrichlorosilane,vinyltriethoxysilane, vinyltrimethoxysilane, vinyltriacetoxysilane andvinyltri(methoxyethoxy)silane. The silane treatment is conducted in theusual manner.

Examples of the polymerization initiator used in the present inventionare room-temperature initiators, e.g. peroxides such as benzoyl peroxideand cumene hydroperoxide; tributylborane; benzoyl peroxide-aromatictertiary amine systems and aromatic sulfinic acids (or saltsthereof)--aromatic secondary or tertiary amine-acyl peroxide systems.Also usable are photopolymerization initiators, e.g. camphorquinone,camphorqunone-tertiary amine systems, camphorquinone-peroxide systems,camphorquinone-aldehyde systems, camphorquinone-mercaptan systems andacylphosphine oxides. Suitably used for photopolymerization by UVirradiation are benzoin methyl ether, benzyl dimethyl ketal,benzophenone, 2-methylthioxanthone, diacetyl, benzyl,azobisisobutyronitrile and tetramethylthiuram disulfide.

The composition of the present invention may, as required, furtherincorporate a polymerization inhibitor, stain, fluorescent agent,UV-absorber or like additives.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1

A dental composite resin (Composition I) was prepared by mixing 17 partsby weight of a mixture consisting of 70 parts by weight of BisGMA, 20parts by weight of triethylene glycol dimethacrylate, 2 parts by weightof an antimicrobial component of the compound 1 shown below, 1 part byweight of camphorquinone and 2 parts by weight of dimethylaminoethylmethacrylate, and 83 parts by weight of a quartz powder surface-treatedwith γ-methacryloytoxypropyltrimethoxysilane and having an averageparticle diameter of 2.4 μm. The composition thus prepared waspolymerized and formed into a disc shaped specimen having a diameter of10 mm and a thickness of 2 mm. The specimen was sterilized with ethyleneoxide gas and then evaluated for antimicrobial activity according to theevaluation methods A, A', B and B'. The results are shown in Table 1.##STR16## Evaluation of antimicrobial activity Evaluation method A

On a prepared BHI (brain heart infusion) agar plate, a culture fluid ofstreptococcus mutans (strain MT 8184) is applied and dried. On the driedplate, a specimen having been evacuated of ethylene oxide gas is placedand incubation is conducted at 37° C. for 48 hours. After completion ofthe incubation, development of bacteria on the bottom surface of thespecimen and that on the surrounding agar region are observed. Theresults are expressed in terms of the following ratings.

a) inhibition of growth of bacteria on the surface of specimen

-: No inhibition at all of bacterial growth beneath the surface ofspecimen. Bacteria have grown uniformly on the entire plate.

±: The effect of inhibiting bacterial growth is slightly observed on theregion on the agar plate just beneath the specimen.

+: Bacterial growth is hardly observed on the region on the agar platejust beneath the specimen.

++: No bacterial growth is observed at all on the region on the agarplate just beneath the specimen.

b) Development of growth-inhibition ring

-: No inhibition ring is observed at all around the specimen.

±: A ring-shaped inhibition of growth is observed around the specimen,the ring having a width of less than 1 mm.

+: A growth-inhibition ring is observed around the specimen, the ringhaving a width of not less than 1 mm and less than 2 mm.

++: A growth-inhibition ring is observed around the specimen, the ringhaving a width of more than 2 mm.

Evaluation method A'

The procedure of evaluation method A is followed with the specimenhaving been immersed in water at 37° C for 1 month.

Evaluation method B

A specimen is hung in a 1×10⁷ CFU/ml solution of streptococcus mutansand containing 1% sucrose. Incubation is conducted at 37° C. for 24hours and then the plaque having deposited on the specimen surface isdyed and judged for the effect of inhibiting plaque deposition, of thespecimen. The results are expressed in terms of the following ratings.

-: Plaque:deposition has hardly been inhibited. No difference in theamount deposited between the specimen and a control containing noantimicrobial component.

±: Plaque deposition has been suppressed to a certain extent.

+: Plaque deposition has been suppressed to a considerable extent.

++: Almost no deposit of plaque is observed on the specimen surface

Evaluation method B'

The procedure of evaluation method B is followed with the specimenhaving been immersed in water at 37° C. for 1 month.

Examples 2 through 6

Example 1 was repeated except that compositions containing the followingcompounds 2 through 6 in lieu of the compound 1 were used instead of thecomposition I. ##STR17##

The results were all good as shown in Table 1, thus proving the factthat antimicrobial polymerizable compounds according to the presentinvention and other than compound 1 are also effective.

Comparative Example 1

Example 1 was repeated except that a composition that is the same ascomposition I but with no compound 1. The results are shown in Table 1.

Comparative Examples 2 through 5

Example 1 was repeated except that compositions containing the followingcompounds 7 through 10 in lieu of the compound 1 were used instead ofthe composition I. The results are shown in Table 1. ##STR18##

                                      TABLE 1    __________________________________________________________________________                         Formation of                                 Inhibition of bacteri-                                           Suppression of                  Content of                         growth-inhibi-                                 al growth beneath                                           plaque deposit on    Example or           Antimicro-                  antimicro-                         tion ring                                 specimen surface                                           specimen surface    Comparative           bial   bial com-                         Method  Method    Method    Example           compound                  pound (wt %)                         A   A'  A    A'   B    B'    __________________________________________________________________________    Example 1           Compound 1                  0.32   -   -   +    +    +    +    Example 2           Compound 2                  0.32   -   -   +    +    +    +    Example 3           Compound 3                  0.32   -   -   ± ± ± ±    Example 4           Compound 4                  0.32   -   -   ± ± ± ±    Example 5           Compound 5                  0.32   -   -   +    +    +    +    Example 6           Compound 6                  0.32   -   -   ± ± ± ±    Comp. Ex. 1            --    --     -   -   -    -    -    -    Comp. Ex. 2           Compound 7                  0.32   ++  -   ++   -    ++   -    Comp. Ex. 3           Compound 8                  0.32   ++  -   ++   -    ++   -    Comp. Ex. 4           Compound 9                  0.32   ++  -   ++   -    ++   -    Comp. Ex. 5           Compound 10                  0.32   ++  -   ++   -    ++   -    __________________________________________________________________________

Examples 7 through 11

Test specimens were prepared from 5 compositions comprising 5 commercialdental materials as shown in Table 2 and incorporating a designatedamount of compound 1 as an antimicrobial composition. The test specimenswere evaluated for antimicrobial activity according to methods A, A', Band B'. The results are shown in Table 2. The antimicrobial compoundused in the present invention is also effective when used in combinationwith commercial dental materials.

Comparative Examples 6 through 10

Test specimens similar to those in Examples 7 through 11 were preparedby using compound 7 instead of compound 1 and evaluated in the samemanner. The results are shown in Table 2.

Comparative Examples b 11 through 15

Examples 7 through 11 were repeated except that the commercial dentalmaterials were used as they were, without addition of the antimicrobialcomponent. The results of evaluation are shown in Table 2.

                                      TABLE 2    __________________________________________________________________________                                                       Inhibition                                                       of bacterial                                                             Suppression                                           Content                                                 Formation                                                       growth                                                             of plaque                                           of    of growth                                                       beneath                                                             deposit on                                           antimi-                                                 inhibition                                                       specimen                                                             specimen    Example or                      Antimicro-                                           crobial                                                 ring  surface                                                             surface    Comparative           Dental material          bial   compound                                                 Method                                                       Method                                                             Method    Example           (supplier)               compound                                           (wt %)                                                 A  A' A  A' B  B'    __________________________________________________________________________    Example 7           Composite resin, PHOTOCLEARFIL A (Kuraray)                                    Compound 1                                           0.3   -  -  +  +  +  +    Example 8           Adhesive, PANAPIA EX (Kuraray)                                    Compound 1                                           0.3   -  -  ++ +  ++ ±    Example 9           Pit & fissure sealant, TEETHMATE (Kuraray)                                    Compound 1                                           0.3   -  -  ++ +  ++ +    Example 10           Denture resin, ACRON (GC)                                    Compound 1                                           0.3   -  -  +  +  +  +    Example 11           Cold-curing resin, UNIFAST (GC)                                    Compound 1                                           0.3   -  -  ++ +  ++ +    Comp. Ex. 6           Composite resin, PHOTOCLEARFIL A (Kurary)                                    Compound 7                                           0.3   ++ -  ++ -  +  -    Comp. Ex. 7           Adhesive, PANAPIA EX (Kuraray)                                    Compound 7                                           0.3   ++ -  ++ -  ++ -    Comp. Ex. 8           Pit & fissure sealant, TEETHMATE (Kuraray)                                    Compound 7                                           0.3   ++ -  ++ -  ++ -    Comp. Ex. 9           Denture resin, ACRON (GC)                                    Compound 7                                           0.3   +  -  +  -  +  -    Comp. Ex. 10           Cold-curing resin, UNIFAST (GC)                                    Compound 7                                           0.3   ++ -  ++ -  ++ -    Comp. Ex. 11           Composite resin, PHOTOCLEARFIL A (Kuraray)                                    --     --    -  -  -  -  -  -    Comp. Ex. 12           Adhesive, PANAPIA EX (Kuraray)                                    --     --    -  -  -  -  -  -    Comp. Ex. 13           Pit & fissure sealant, TEETHMATE (Kuraray)                                    --     --    -  -  -  -  -  -    Comp. Ex. 14           Denture resin, ACRON (GC)                                    --     --    -  -  -  -  -  -    Comp. Ex. 15           Cold-curing resin, UNIFAST (GC)                                    --     --    -  -  -  -  -  -    __________________________________________________________________________

Example 12

A composition comprising 96.7 parts by weight of 2-hydroxyethylmethacrylate (HEMA), 3 parts by weight of compound 1 and 0.3 part byweight of ethylene glycol dimethacrylate was subjected to bulkpolymerization with an azobis-based polymerization initiator (V-601), togive a polymer for soft contact lens. The polymer is formed into a platehaving a diameter of 10 mm and a thickness of 0.1 mm, which was thenevaluated for antimicrobial activity according to the following methods.

Evaluation method C

Paecilomyces lilacinus, which often develops on soft contact lens, wasseparated, pre-incubated and prepared into a spore fluid. The sporefluid was applied onto a plate PDA culture medium (potato, dextrose andagar). The specimen was placed on the PDA plate and incubation was thenconducted at 27° C. for 7 days. After completion of the incubation,development of bacteria on and around the bottom surface of the specimenwas observed. The results are expressed in terms of the followingratings.

a) Inhibition of bacteria growth on the surface of specimen

-: No inhibition at all of bacterial growth on the surface of specimenor on the agar plate just beneath the specimen.

±: The effect of inhibiting bacterial growth is slightly observed on theregion on the surface of specimen and on the agar plate just beneath thespecimen.

+: Bacterial growth is hardly observed on the surface of the specimen oron the agar plate just beneath the specimen.

b) Development of growth-inhibition ring

-: No inhibition of growth is observed at all around the specimen.

±: A vague growth-inhibition ring is observed around the specimen.

+: Growth-inhibition ring is clearly observed around the specimen.

Evaluation method C'

The procedure of evaluation method C is followed with the specimenhaving been immersed in water at 37° C. for 1 month.

The results are shown in Table 3.

Examples 13 through 17

Example 12 was repeated except that compounds 2 through 6 were usedinstead of compound 1. The results are shown in Table 3. Compositionscontaining other antimicrobial compounds and according to the presentinvention also give good results.

Comparative Example 16

Example 12 was repeated except that HEMA was used instead of compound 1.The evaluation results are shown in Table 3.

Comparative Examples 17 through 20

Example 12 was repeated except that compounds 7 through 10 were usedinstead of compound 1. The results are shown in Table 3.

                                      TABLE 3    __________________________________________________________________________                                    Inhibition of bacterial                  Content of                         Formation of growth-                                    growth beneath specimen    Example or           Antimicro-                  antimicro-                         inhibition ring                                    surface    Comparative           bial   bial com-                         Method     Method    Example           compound                  pound (wt %)                         C    C'    C      C'    __________________________________________________________________________    Example 12           Compound 1                  3.0    -    -     +      +    Example 13           Compound 2                  3.0    -    -     +      +    Example 14           Compound 3                  3.0    -    -     ±   ±    Example 15           Compound 4                  3.0    -    -     ±   ±    Example 16           Compound 5                  3.0    -    -     +      +    Example 17           Compound 6                  3.0    -    -     ±   ±    Comp. Ex. 16            --    --     -    -     -      -    Comp. Ex. 17           Compound 7                  3.0    +    -     +      -    Comp. Ex. 18           Compound 8                  3.0    +    -     +      -    Comp. Ex. 19           Compound 9                  3.0    +    -     +      -    Comp. Ex. 20           Compound 10                  3.0    +    -     +      -    __________________________________________________________________________

Example 18

Evaluation method D

Pseudomonas aeruginosa, which is often found in cornea infection ofcontact lens wearers, is separated and preincubated. The bacterialliquid was applied onto a plate of BHI (brain heart infusion) agarculture medium. The same specimen as in Example 12 was placed on the BHIplate and incubation was then conducted at 37° C. for 48 hours. Aftercompletion of the incubation, development of bacteria on and around thebottom surface of the specimen are observed. The results are expressedin terms of the same ratings as those for evaluation method C. Theresults are shown in Table 4.

Evaluation method D'

The procedure of evaluation method D is followed with the specimenhaving been immersed in water at 37° C. for 1 month. The results areshown in Table 4.

Example 19

Example 18 was repeated except that Staphylococcus epidermidis was usedfor evaluation instead of the P. aeruginosa used in Example 18. Theevaluation results are shown in Table 4.

Example 20

Example 18 was repeated except that Streptococcus pyogenes was used forevaluation instead of P. aeruginosa. The evaluation results are shown inTable 4.

Comparative Examples 21 through 23

Example 18 (Example 12) was repeated except that HEMA was used insteadof compound 1, to prepare a specimen. The specimen was evaluated by thesame procedures as in Examples 18 through 20. The results are shown inTable 4.

Comparative Examples 24 through 26

Example 18 (Example 12) was repeated except that compound 7 was usedinstead of compound 1, to prepare a specimen. The specimen was evaluatedby the same procedures as in Examples 18 through 20. The results areshown in Table 4.

                                      TABLE 4    __________________________________________________________________________                                           Inhibition of bacterial                  Content of    Formation of growth-                                           growth beneath specimen    Example or           Antimicro-                  antimicro-    inhibition ring                                           surface    Comparative           bial   bial com-                         Bacterium                                Method     Method    Example           compound                  pound (wt %)                         used   D    D'    D      D'    __________________________________________________________________________    Example 12           Compound 1                  3.0    P. lilacinus                                -    -     +      +    Example 18           Compound 1                  3.0    P. aeruginosa                                -    -     ±   ±    Example 19           Compound 1                  3.0    S. epidermidis                                -    -     +      +    Example 20           Compound 1                  3.0    S. pyogenes                                -    -     +      +    Comp. Ex. 16            --    --     P. lilacinus                                -    -     -      -    Comp. Ex. 21            --    --     P. aeruginosa                                -    -     -      -    Comp. Ex. 22            --    --     S. epidermidis                                -    -     -      -    Comp. Ex. 23            --    --     S. pyogenes                                -    -     -      -    Comp. Ex. 24           Compound 7                  3.0    P. aeruginosa                                +    -     +      -    Comp. Ex. 25           Compound 7                  3.0    S. epidermidis                                +    -     +      -    Comp. Ex. 26           Compound 7                  3.0    S. pyogenes                                +    -     +      -    __________________________________________________________________________

Examples 21 through 23

A composition comprising 67 parts by weight of methyl methacrylate(MMA), 30 parts by weight of siloxanyl methacrylate and 3 parts byweight of compound 1 was subjected to bulk polymerization with anazobis-based polymerization initiator (V-601), to obtain a polymer forhard contact lens. The polymer is formed into a plate having a diameterof 10 mm and a thickness of 0.2 mm, which was then evaluated in the samemanner as in Examples 18 through 20 (evaluation method D and D'). Theresults are shown in Table 5.

Comparative Examples 27 through 29

Example 21 was repeated except that compound 1 was replaced by MMA, toobtain a specimen. The specimen was evaluated in the same manner as inExamples 21 through 23. The results are shown in Table 5.

Comparative Examples 30 through 32

Example 21 was repeated except that compound 7 was used instead ofcompound 1, to obtain a specimen, which was then evaluated in the samemanner as in Examples 21 through 23. The results are shown in Table 5.

                                      TABLE 5    __________________________________________________________________________                                           Inhibition of bacterial                  Content of    Formation of growth-                                           growth beneath specimen    Example or           Antimicro-                  antimicro-    inhibition ring                                           surface    Comparative           bial   bial com-                         Bacterium                                Method     Method    Example           compound                  pound (wt %)                         used   D    D'    D      D'    __________________________________________________________________________    Example 21           Compound 1                  3.0    P. aeruginosa                                -    -     +      +    Example 22           Compound 1                  3.0    S. epidermidis                                -    -     ±   ±    Example 23           Compound 1                  3.0    S. pyogenes                                -    -     +      +    Comp. Ex. 27            --    --     P. aeruginosa                                -    -     -      -    Comp. Ex. 28            --    --     S. epidermidis                                -    -     -      -    Comp. Ex. 29            --    --     S. pyogenes                                -    -     -      -    Comp. Ex. 30           Compound 7                  3.0    P. aeruginosa                                +    -     +      -    Comp. Ex. 31           Compound 7                  3.0    S. epidermidis                                +    -     +      -    Comp. Ex. 32           Compound 7                  3.0    S. pyogenes                                +    -     +      -    __________________________________________________________________________

Example 24

A bone cement comprising the following powder agent and liquid agent wastentatively prepared. The powder agent and the liquid agent were mixedin a ratio of 2/1 (g/ml) and the mixture was put into a split moldhaving a diameter and thickness of 10 mm and 3 mm, respectively, andcured therein. The cured article was allowed to stand at 37° C. for 1day and then evaluated in the same manner as in Example 20. The resultsare shown in Table 6.

Powder agent

Polymethyl methacrylate (PMMA): 89 parts by weight

Barium sulfate: 10 parts by weight

Benzoyl peroxide: 1 part by weight

Liquid agent

Methyl methacrylate (MMA): 88 parts by weight

Compound 1: 10 parts by weight

N,N-diethanol-p-toluidine: 2 parts by weight

Examples 25 through 29

Example 24 was repeated except that each of compounds 2 through 6 wasused instead of compound 1. The evaluation results are shown in Table 6.

Example 30

A composition comprising 95 parts by weight of MMA and 5 parts by weightof compound 1 was emulsion-polymerized to give a particulate polymer(polymer A). The polymer thus obtained was used to prepare the followingbone cement tentatively, which was evaluated in the same manner as inExample 24. The results are shown in Table 6.

Powder agent

Polymer (A): 89 parts by weight

Barium sulfate: 10

Benzoyl peroxide: 1 part by weight

Liquid agent

MMA: 98 parts by weight

N,N-diethanol-p-toluidine: 2 parts by weight

Examples 31 through 33

Example 30 was repeated except that each of compounds 2, 4 and 5 wasused instead of compound 1. The evaluation results are shown in Table 6.

Comparative Example 33

Example 24 was repeated except that compound 1 in the liquid agent wasreplaced by MMA. The evaluation results are shown in Table 6.

Comparative Examples 34 through 37

Example 24 was repeated except that compound 1 in the liquid agent wasreplaced by each of compounds 7 through 10. The evaluation results areshown in Table 6.

                                      TABLE 6    __________________________________________________________________________                                    Inhibition of bacterial                  Content of                         Formation of growth-                                    growth beneath specimen    Example or           Antimicro-                  antimicro-                         inhibition ring                                    surface    Comparative           bial   bial com-                         Method     Method    Example           compound                  pound (wt %)                         C    C'    C      C'    __________________________________________________________________________    Example 24           Compound 1                  about 3.0                         -    -     +      +    Example 25           Compound 2                  about 3.0                         ± -     +      +    Example 26           Compound 3                  about 3.0                         -    -     +      +    Example 27           Compound 4                  about 3.0                         ± -     ±   ±    Example 28           Compound 5                  about 3.0                         -    -     +      +    Example 29           Compound 6                  about 3.0                         -    -     +      +    Example 30           Compound 1                  about 3.0                         -    -     +      +    Example 31           Compound 2                  about 3.0                         -    -     +      +    Example 32           Compound 4                  about 3.0                         -    -     +      +    Example 33           Compound 5                  about 3.0                         -    -     +      +    Comp. Ex. 33            --    --     -    -     -      -    Comp. Ex. 34           Compound 7                  about 3.0                         +    -     +      -    Comp. Ex. 35           Compound 8                  about 3.0                         +    -     +      -    Comp. Ex. 36           Compound 9                  about 3.0                         +    -     +      -    Comp. Ex. 37           Compound 10                  about 3.0                         +    -     +      -    __________________________________________________________________________

Examples 34 through 36

In 100 ml of water was dissolved 5 g of compound 1. In the obtainedsolution 5 g of a collagen nonwoven fabric was immersed. To the mixture,2.5 ml of 1N nitric acid containing 0.1 mole/l of ammonium-ceriumnitrate was added, and polymerization was effected at 20° C. under anatmosphere of nitrogen for 10 hours. The nonwoven fabric thus treatedwas repeatedly washed with water and acetone, to give wound-coveringmaterial (artificial skin) comprising a collagen nonwoven fabric towhich compound 1 has been graft-polymerized. The material thus obtainedwas cut to square sheets of 10×10 mm, which Were then evaluated forantimicrobial activities in the same manner as in Examples 18 through 20(by evaluation methods D and D'). The results are shown in Table 7.

Examples 37 through 41

Example 34 was repeated except that compounds 2 through 6 were each usedinstead of compound 1. The evaluation results are shown in Table 7.

Comparative Example 7

Example 34 was repeated except that the collagen nonwoven fabric wasused as it was. The results are shown in Table 7.

                                      TABLE 7    __________________________________________________________________________                                    Inhibition of bacterial                         Formation of growth-                                    growth beneath specimen    Example or           Antimicro-    inhibition ring                                    surface    Comparative           bial   Bacterium                         Method     Method    Example           compound                  used   D    D'    D      D'    __________________________________________________________________________    Example 34           Compound 1                  P. aeruginosa                         -    -     +      +    Example 35           Compound 1                  S. epidermidis                         -    -     ±   ±    Example 36           Compound 1                  S. pyogenes                         -    -     +      +    Example 37           Compound 2                  P. aeruginosa                         -    -     +      +    Example 38           Compound 3                  P. aeruginosa                         -    -     +      +    Example 39           Compound 4                  P. aeruginosa                         -    -     ±   ±    Example 40           Compound 5                  P. aeruginosa                         -    -     +      +    Example 41           Compound 6                  P. aeruginosa                         -    -     ±   ±    Comp. Ex. 38            --    P. aeruginosa                         -    -     -      -    __________________________________________________________________________

Example 42

A composition comprising 80 parts by weight of methyl methacrylate (MMA)and 20 parts by weight of compound 1 was subjected to bulkpolymerization with an azobis-based polymerization initiator (V-601), togive a polymer having a number average polymerization degree of about50,000. To remove residual monomers, the polymer obtained was dissolvedin methylene chloride, and reprecipitated from hexane and collected byfiltration. The thus purified polymer was named polymer-B. A 5% byweight solution of the polymer-B in methylene chloride was prepared. Apolyvinyl chloride catheter was immersed in the thus prepared solution.The catheter was then taken out and the adhering methylene chloride wassufficiently evaporated off, to give a catheter surface-coated withpolymer-B. The thus surface-treated catheter and an untreated catheterwere compared for antimicrobial activities according to the followingmethod.

Evaluation method E

Staphylococcus epidermidis is separated and pre-incubated. The bacterialiquid is inoculated on a BHI culture medium. A specimen is immersed inthe thus prepared liquid culture medium and aerobic incubation isconducted at 37° C. for 48 hours. The specimen is taken out and gramstained. The condition of bacterial growth on the specimen surface isobserved and judged according to the following ratings.

-: No inhibition at all of bacterial growth on the surface of thespecimen (bacteria have grown to the same extent as or even largerextent than on the surface of the untreated specimen).

±: The effect of inhibiting bacterial growth is slightly observed on thesurface of specimen, i.e. bacteria have grown to a smaller extent thanwith the untreated specimen.

+: Bacterial growth is hardly observed on the surface of the specimen.

The results of evaluation are shown in Table 8.

Examples 43 th rough 45

Example 42 was repeated except that a suture (made of silk), anartificial skin (made of formalized polyvinyl alcohol) or an artificialvessel (made of segmented polyurethane) w-as used instead of thecatheter used in Example 42. The evaluation results are shown in Table8.

Comparative Examples 39 through 42

Examples 42 through 45 were repeated except that PMMA (polymethylmethacrylate) was used instead of polymer-B. The results are shown inTable 8.

                  TABLE 8    ______________________________________                                   Inhibition of bac-                        Content of terial growth on    Example or             Antimicro- antimicro- specimen surface    Comparative             bial       bial com-  Evaluation    Example  compound   pound (wt %)                                   method E    ______________________________________    Example 42             Compound 1 20         +    Example 43             Compound 1 20         +    Example 44             Compound 1 20         +    Example 45             Compound 1 20         ±    Comp. Ex. 39             --         -          -    Comp. Ex. 40             --         -          -    Comp. Ex. 41             --         -          -    Comp. Ex. 42             --         -          -    ______________________________________

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. A polymerizable composition comprising anethylenically unsaturated monomer, at least one di- or trifunctionalmonomer in an amount of 0.01 to 50% by weight selected from the grouprepresented by the following formulas II and III and havingantimicrobial activity, and a polymerization initiator ##STR19## whereinR₁ represents a hydrogen atom or a methyl group, R₂ represents analkylene group having 2 to 18 carbon atoms, X represents an oxygen atom,a sulfur atom or an imide group and Y' and Y" represent any one selectedfrom the following respective formulas: ##STR20## wherein R₃ representsa hydrogen atom or an alkyl group having 1 to 18 carbon atoms, R₄represents a methyl group, an ethyl group or a hydroxyethyl group and Zrepresents a chlorine atom or bromine atom.
 2. An antimicrobialcrosslinked copolymer obtained by polymerizing a mono- ormultifunctional ethylenically unsaturated monomer and an antimicrobialmonomer represented by the above formula II or III.
 3. An insolubleantimicrobial medical article obtained by shaping the polymer of claim2.